Bi-allelic recessive loss-of-function mutations in FIGLA cause premature ovarian insufficiency with short stature
Bi-allelic recessive loss-of-function mutations in FIGLA cause premature ovarian insufficiency with short stature
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FigLA双等位基因隐性功能丧失突变导致卵巢早衰和身材矮小
DOI：
10.1111/cge.13486
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发表时间：
2019-03-01
影响因子：
3.5
通讯作者：
Yang, Dongzi
中科院分区：
文献类型：
--
作者：
Yuan, Ping;He, Zuyong;Yang, Dongzi
卵巢早衰是一组异质性疾病，其特征是卵巢储备功能下降和促卵泡激素（FSH）水平升高。它很少与身材矮小有关。FIGLA中带有POI的突变是从杂合性方面进行鉴定的;迄今为止，只有一个受影响的家族被鉴定出带有FIGLA中的纯合突变，但没有进行功能评估。在这里，我们描述了两个POI患者从一个血缘家庭来自中国。一位18岁的女孩和她的妹妹表现为原发性闭经和FSH和黄体生成素水平升高，但妹妹也表现为身材矮小和骨龄延迟。全基因组测序分析确定了FIGLA基因中的一个复发性纯合突变，c.2 T > C（p.Met1Thr），在该POI家族成员中;该变体在家系中分离。在382名对照受试者中没有这种变化，我们在其他39名特发性POI患者中没有检测到任何突变。体外功能分析表明，p.Met1Thr突变不影响FIGLA基因的转录，但阻断全长FIGLA蛋白的合成。我们的研究结果支持这样的观点，即FIGLA的双等位基因隐性功能丧失效应导致身材矮小的POI患者，并扩大了FIGLA相关的表型谱。
Premature ovarian insufficiency (POI) is a group of heterogeneous disorders characterized by decreased ovarian reserve and increased follicle stimulating hormone (FSH) levels. It is rarely associated with short stature. FIGLA mutations with POI are identified with regard to heterozygosity; till date, only one affected family has been identified with homozygous mutations in FIGLA but without functional evaluation. Here, we described two POI patients from a consanguineous family from China. An 18-year-old girl and her sister presented with primary amenorrhea and increased FSH and luteinizing hormone levels, but the sister also presented with short stature and bone age delay. Whole-genome sequencing analysis identified a recurrent homozygous mutation in the FIGLA gene, c.2 T > C (p.Met1Thr), in this family member with POI; this variant was segregated within the pedigree. This change was absent in 382 control subjects, and we did not detect any mutations in 39 other idiopathic POI patients. in vitro functional analysis indicates that the p.Met1Thr mutation does not affect the transcription of the FIGLA gene, but blocks the synthesis of the full-length FIGLA protein. Our results support the notion that bi-allelic recessive loss-of-function effects of FIGLA contribute to POI patients with short stature and expand the FIGLA-related phenotypic spectrum.